Myofibroblast fate plasticity in tissue repair and fibrosis: Deactivation, apoptosis, senescence and reprogramming

Abstract

In response to tissue injury, fibroblasts differentiate into professional repair cells called myofibroblasts, which orchestrate many aspects of the normal tissue repair programme including synthesis, deposition and contraction of extracellular matrix proteins, leading to wound closure. Successful tissue repair responses involve termination of myofibroblast activities in order to prevent pathologic fibrotic scarring. Here, we discuss the cellular and molecular mechanisms limiting myofibroblast activities during physiological tissue repair, including myofibroblast deactivation, apoptosis, reprogramming and immune clearance of senescent myofibroblasts. In addition, we summarize pathological mechanisms leading to myofibroblast persistence and survival, a hallmark of fibrotic diseases. Finally, we discuss emerging anti-fibrotic therapies aimed at targeting myofibroblast fate such as senolytics, gene therapy, cellular immunotherapy and CAR-T cells.

Keywords: apoptosis; cellular senescence; fate; fibrosis; myofibroblast; plasticity; reprogramming; tissue repair.

FIGURE 1

Myofibroblast fate upon termination of the tissue repair programme. Following tissue injury, extracellular matrix (ECM) breakdown and inflammatory cytokines such as TGFb promote fibroblast differentiation into activated myofibroblasts, which are characterized by increased synthesis of ECM and the neo-expression of alpha smooth muscle actin (α-SMA), a protein that confers these cells a hyper-contractile phenotype. These two cellular activities are essential for promoting wound closure and reepithelialization. Successful tissue repair responses involve termination of myofibroblast activities via alternative mechanisms including deactivation, apoptosis, immune clearance of senescent myofibroblasts by T and natural killer (NK) cells and reprograming

FIGURE 2

Targeting myofibroblast fate for the treatment of established fibrosis. Myofibroblast persistence is a hallmark of fibrotic diseases characterized by progressive tissue scarring. The molecular mechanisms that promote myofibroblast persistence include pathological growth factor signalling (e.g. TGF-β pathway), mechanical signalling induced by matrix stiffness, cellular senescence and the senescence-associated secretory phenotype (SASP: TGF-β, IL6, IL8) as well as metabolic and epigenetic reprogramming. This knowledge has paved the way for new therapeutic strategies aiming at reversing fibrosis by targeting myofibroblast fate and promoting myofibroblast apoptosis and immune clearance, deactivation and reprogramming. These novel treatments include senolytics, gene therapy, cellular immunotherapy and CAR-T cells, and may not only reverse fibrosis but also regenerate fibrotic tissues